Dihydropyridine derivative, and pharmaceutical composition comprising the same

ABSTRACT

1,4-dihydropyridine derivatives of the general formula: ##STR1## having vasodilating and anti-hypertensive activity, processes for preparing same, and pharmaceutical compositions thereof for treating cardiovascular diseases.

This is a division of application Ser. No. 70,098, filed Aug. 27, 1979,now U.S. Pat. No. 4,307,103 issued Dec. 22, 1981.

This invention relates to a dihydropyridine derivative and a saltthereof. More particularly, it relates to a new dihydropyridinederivative and a pharmaceutically acceptable salt thereof which havevasodilating and anti-hypertensive activities, to processes for thepreparation thereof, and to pharmaceutical composition comprising thesame for therapeutical treatment of cardiovascular disorder andhypertension in human being.

With regard to the states of the arts in this field, for example, thefollowing dihydropyridine compounds are known. ##STR2##

One object of this invention is to provide the new and usefuldihydropyridine derivative and the pharmaceutically acceptable saltthereof, which are structurally characterized in the substituent(s) atthe third and/or sixth positions of the dihydropiridine nucleus and havestronger activity as compared with the known compounds, for example, asshown above, especially in anti-hypertensive activity.

Another object of this invention is to provide processes for thepreparation of the dihydropyridine derivative and the salt thereof.

A further object of this invention is to provide an usefulpharmaceutical composition comprising, as an active ingredient, saiddihydropyridine derivative or the pharmaceutically acceptable saltthereof, which is useful as a vasodilator and anti-hypertensive agents,especially, anti-hypertensive agent.

Still further object of the present invention is to provide atherapeutical method for treatment of cardiovascular disorder such ascoronary insufficiency, angina pectoris or myocardial infarction andhypertension.

The dihydropyridine derivative of this invention can be represented bythe formula: ##STR3## wherein R¹ is nitro, halogen, loweralkoxycarbonyl, cyano, trihalo(lower)alkyl or phenyl,

R² is lower alkyl; [N-loweralkyl-N-haloar(lower)alkyl]amino(lower)alkyl; [N-lower alkyl-N-loweralkylar(lower)alkyl]amino(lower)alkyl; [N-lower alkyl-N-loweralkoxyar(lower)alkyl]amino(lower)alkyl; aroylamino(lower)alkyl,saturated N-containing heterocyclic(lower)alkyl, in which theN-containing heterocyclic moiety is always linked by the nitrogen atomto the lower alkyl moiety; heterocyclic-thio(lower)alkyl; loweralkanoyloxy(lower)alkyl; lower alkylthio(lower)alkyl;ar(lower)alkylthio(lower)alkyl; or arylthio(lower)alkyl,

R³ is lower alkyl,

R⁴ is lower alkyl and

R⁵ is cyano, formyl, di(lower)alkoxymethyl, hydroxymethyl,halo(lower)alkanoyloxymethyl, lower alkanoyloxymethyl, loweralkoxyaroyloxymethyl, heterocycliccarbonyloxymethyl, loweralkanoyl(lower)alken-1-yl, halo(lower)alken-1-yl,cyano(lower)alken-1-yl, hydroxy(lower)alken-1-yl or lower alkyn-1-yl,

provided that

when R¹ is nitro, halogen or trihalo(lower)alkyl and R² is lower alkyl,

then R⁵ is halo(lower)alkanoyloxymethyl, lower alkoxyaroyloxymethyl,heterocycliccarbonyloxymethyl, lower alkanoyl(lower)alken-1-yl,halo(lower)alken-1-yl, cyano(lower)alken-1-yl, hydroxy(lower)alken-1-ylor lower alkyn-1-yl, and

when R¹ is cyano or lower alkoxycarbonyl and R² is lower alkyl,

then R⁵ is halo(lower)alkanoyloxymethyl, lower alkanoyloxymethyl, loweralkoxyaroyloxymethyl, heterocycliccarbonyloxymethyl, loweralkanoyl(lower)alken-1-yl, halo(lower)alken-1-yl,cyano(lower)alken-1-yl, hydroxy(lower)alken-1-yl or lower alkyn-1-yl.

With regard to the object compound of the above formula (I), it is to beunderstood that the compound (I) represents inclusively all of thepossible optical and/or geometrical isomers due to the asymmetric carbonatoms(s) and/or carbon-carbon double bond in the group for R⁵ in themolecule of the compound (I), and accordingly such optical and/orgeometrical isomers are also included within the scope of the presentinvention.

According to this invention, the object compound (I) can be prepared bythe process as illustrated by the following reaction schemes.

(1) Process 1: ##STR4## wherein R¹, R³, R⁴ and R⁵ are each as definedbefore,

R_(a) ² is halo(lower)alkyl,

R_(b) ² is [N-lower alkyl-N-haloar(lower)alkyl]amino(lower)alkyl;[N-lower alkyl-N-lower alkylar(lower)alkyl]amino(lower)alkyl; [N-loweralkyl-N-lower alkoxyar(lower)alkyl]amino(lower)alkyl;aroylamino(lower)alkyl; saturated N-containing heterocyclic(lower)alkyl,in which the N-containing heterocyclic moiety is always linked by thenitrogen atom to the lower alkyl moiety; orheterocyclic-thio(lower)alkyl and

R^(a) is N-lower alkyl-N-haloar(lower)alkyl]amino; [N-loweralkyl-N-lower alkylar(lower)alkyl]amino, N-lower alkyl-N-loweralkoxyar(lower alkyl)amino; aroylamino; saturated N-containingheterocyclic group; or heterocyclic-thio.

(2) Process 2: ##STR5## wherein R¹, R³ and R⁴ are each as definedbefore,

R_(c) ² is [N-lower alkyl-N-haloar(lower)alkyl]amino(lower)alkyl;[N-lower alkyl-N-lower alkylar(lower)alkyl]amino(lower)alkyl; [N-loweralkyl-N-lower alkoxyar(lower)alkyl]amino(lower)alkyl;aroylamino(lower)alkyl; saturated N-containing heterocyclic(lower)alkyl,in which the N-containing heterocyclic moiety is always linked by thenitrogen atom to the lower alkyl moiety; heterocyclicthio(lower)alkyl;lower alkanoyloxy(lower)alkyl; lower alkylthio(lower)alkyl,ar(lower)alkylthio(lower)alkyl or arylthio(lower)alkyl and

R_(a) ⁵ is di(lower)alkoxymethyl.

(3) Process 3: ##STR6## wherein R¹, R_(c) ², R³ and R⁴ are each asdefined before, and

R_(d) ² is [N-lower alkyl-N-haloar(lower)alkyl]amino(lower)alkyl;[N-lower alkyl-N-lower alkylar(lower)alkyl]amino(lower)alkyl; [N-loweralkyl-N-lower alkoxyar(lower)alkyl]amino(lower)alkyl;aroylamino(lower)alkyl; saturated N-containingheterocyclic-(lower)alkyl, in which the N-containing heterocyclic moietyis always linked by the nitrogen atom to the lower alkyl;heterocyclicthio(lower)alkyl; hydroxy(lower)alkyl; loweralkylthio(lower)alkyl; ar(lower)alkylthio(lower)alkyl, orarylthio(lower)alkyl.

(4) Process 4: ##STR7## wherein R¹, R_(c) ², R³ and R⁴ are each asdefined before,

R_(b) ⁵ is formyl or lower alkanoyl(lower)alken-1-yl, and

R_(c) ⁵ is hydroxymethyl or hydroxy(lower)alken-1-yl.

(5) Process 5: ##STR8## wherein R¹, R², R³ and R⁴ are each as definedbefore, and

R^(b) is lower alkanoyl, halo(lower)alkanoyl, lower alkoxyaroyl orheterocyclic-carbonyl, provided that when R¹ is nitro, halogen ortrihalo(lower)alkyl and R² is lower alkyl, then R^(b) ishalo(lower)alkanoyl, lower alkoxyaroyl or heterocyclic-carbonyl, andwhen R¹ is cyano or lower alkoxycarbonyl, then R^(b) ishalo(lower)alkanoyl, lower alkanoyl, lower alkoxyaroyl orheterocycliccarbonyl.

(6) Process 6: ##STR9## wherein R¹, R², R³ and R⁴ are each as definedbefore,

R_(d) ⁵ is lower alkanoyl(lower)alken-1-yl, halo(lower)alken-1-yl orcyano(lower)alken-1-yl,

R^(c) is aryl or lower alkyl,

R^(d) is hydrogen or halogen, and

R^(e) is lower alkanoyl, halogen or cyano.

(7) Process 7: ##STR10## wherein R¹, R², R³ and R⁴ are each as definedbefore,

R_(e) ⁵ is lower alkyn-1-yl, and

X is halogen.

Process 8 ##STR11## wherein R¹, R³, R⁴ and R_(a) ⁵ are each as definedbefore, and R_(e) ² is lower alkylthio(lower)alkyl,ar(lower)alkylthio(lower)alkyl and arylthio(lower)alkyl.

Process 9 ##STR12## wherein R³, R⁴ and R_(a) ⁵ are each as definedbefore, R^(1') is phenyl and R_(f) ² is lower alkyl.

Detailed explanation for the definitions used throughout thisspecification will be made and the suitable examples thereof will beillustrated in the following.

The term "lower" used in connection with all of the alkane, alkene andalkyne moieties is intended to mean 1 to 8 carbon atoms, preferably 1 to6 carbon atoms, and more preferably 1 to 4 carbon atoms.

"Halogen" for R¹, R^(d), R^(e) and X includes fluorine, chlorine,bromine, iodine, and preferred one is chlorine and bromine.

"Lower alkoxycarbonyl" for R¹ can also be represented by the formula:-co-o-(lower)alkyl, wherein the lower alkyl group includes monovalentradical of straight- and branched-chain(lower)alkanes. Suitable loweralkoxycarbonyl includes methoxycarbonyl, ethoxycarbonyl,propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, t-butoxycarbonyland the like, and more preferably methoxycarbonyl.

"Lower alkyl" for R², R_(f) ², R³, R⁴ and R^(c) includes a monovalentradical of straight- and branched-chain(lower)alkanes, and suitablelower alkyl group includes methyl, ethyl, propyl, isopropyl, butyl,isobutyl, t-butyl, pentyl, neopentyl, hexyl, heptyl, octyl and the like,more preferably C₁ -C₄ alkyl group, and preferred one is methyl andethyl.

"Trihalo(lower)alkyl" for R¹ preferably includes trihalomethyl such astrifluoromethyl or the like.

"[N-(lower)alkyl-N-haloar(lower)alkyl]amino(lower)alkyl" for R², R_(b)², R_(c) ² and R_(d) ² is intended to mean a lower alkyl which alwaysbears [N-lower alkyl-N-haloar(lower)alkyl]amino group and particularlyincludes [N-lower alkyl-N-monohaloar(lower)alkyl]amino(lower)alkyl,preferred example of which may be [N-loweralkyl-N-monohalophenyl(lower)alkyl]amino(lower)alkyl such as N-loweralkyl-N-monohalobenzylamino(lower)alkyl [e.g. N-methyl-N-(2- or 3- or4-chlorobenzyl)aminomethyl, 1-or 2-[N-methyl-N-(2- or 3- or4-chlorobenzyl)amino]ethyl, 1- or 2-[N-ethyl-N-(2- or 3- or4-chlorobenzyl)amino]ethyl, 1- or 2- or 3-[N-propyl-N-(2- or 3- or4-chlorobenzyl)amino]propyl, 1- or 2-[N-methyl-N-(2- or 3- or4-bromobenzyl)amino]ethyl, etc.;[N-(lower)alkyl-N-dihaloar(lower)alkylamino](lower)alkyl, preferredexample of which may be [N-loweralkyl-N-dihalophenyl(lower)alkyl]amino(lower)alkyl such as N-loweralkyl-N-dihalobenzylamino(lower)alkyl [e.g. N-methyl-N-(2,3- or 3,4- or2,4- or 3,5- dichlorobenzyl)aminomethyl, 1- or 2-[N-methyl-N-(2,3- or3,5 - or 2,4- or 3,4-dichlorobenzyl)amino]ethyl, 1- or2-[N-ethyl-N-(2,3- or 3,4- or 2,4- or 3,5-dichlorobenzyl)amino]ethyl, 1-or 2- or 3-[N-propyl-N-(2,3- or 3,4- or 2,4- or3,5-dibromobenzyl)aminopropyl, etc.,] and the like, and particularlypreferred one is 2-[N-methyl-N-(4-chlorobenzyl)amino]ethyl and2-[N-methyl-N-(3,4-dichlorobenzyl)amino]ethyl.

"[N-lower alkyl-N-lower alkylar(lower)alkyl]amino(lower)alkyl" for R²,R_(b) ², R_(c) ² and R_(d) ² is intended to mean a lower alkyl whichalways bears [N-lower alkyl-N-lower alkylar(lower)alkyl]amino group andparticularly includes [N-lower alkyl-N-loweralkylphenyl(lower)alkyl]amino(lower)alkyl such as N-lower alkyl-N-loweralkylbenzylamino(lower)alkyl (e.g. N-methyl-N-(2- or 3- or4-methylbenzyl)aminomethyl, 1- or 2-[N-methyl-N-(2- or 3- or4-methylbenzyl)amino]ethyl, 1- or 2- or 3-[N-propyl-N-(2- or 3- or 4-ethylbenzyl)amino]propyl, etc.) or the like, and particularly preferredone is 2-[N-methyl-N-(4-methylbenzyl)amino]ethyl.

"[N-lower alkyl-N-lower alkoxyar(lower)alkyl]amino(lower)alkyl" for R²,R_(b) ², R_(c) ² and R_(d) ² is intended to mean a lower alkyl whichalways bears [N-lower alkyl-N-lower alkoxyar(lower)alkyl]amino group andparticularly includes [N-lower alkyl-N-loweralkoxyphenyl(lower)alkylamino](lower)alkyl such as N-lower alkyl-N-loweralkoxybenzylamino(lower)alkyl [e.g. N-methyl-N-(2- or 3- or4-methoxybenzyl)aminomethyl, 1- or 2-[N-methyl-N-(2- or 3- or4-methoxybenzyl)amino]ethyl, 1- or 2- or 3-[N-propyl-N-(2- or 3- or4-ethoxybenzyl)amino]propyl, etc.,] or the like, and particularlypreferred one is 2-[N-methyl-N-(4-methoxybenzyl)amino]ethyl.

"Aroylamino(lower)alkyl" for R², R_(b) ², R_(c) ² and R_(d) ² isintended to mean a lower alkyl which always bears an aroylamino group,in which aroylamino group includes monobasic or dibasic aromaticcarbonylamino and-imino groups including aroylamino(lower)alkyl such asbenzamidomethyl, 1- or 2-benzamidoethyl, 1- or 2-toluamidoethyl or thelike, and aroylimino(lower)alkyl such as phthaliminomethyl, 1- or2-phthalimidoethyl, 1- or 2- or 3-phthalimidopropyl, or the like, andparticularly preferred one is 2-phthalimidoethyl.

"Saturated N-containing heterocyclic-(lower)alkyl, in which theN-containing heterocyclic moiety is always linked by the nitrogen atomto the lower alkyl moiety" for R², R_(b) ², R_(c) ² and R_(d) ² isparticularly intended to mean a lower alkyl group which always bonds to5 or 6-membered saturated N-containing heterocyclic moiety via thenitrogen atom thereof, in which the N-containing heterocyclic group mayfurther contain at least one hetero-atom selected from two nitrogen atomand oxygen atom. Suitable examples of 5 or 6-membered saturatedN-containing heterocyclic-(lower)alkyl include morpholino(lower)alkylsuch as morpholinomethyl, 1, or 2-morpholinoethyl, 1- or 2- or3-morpholinopropyl, 1- or 2-, 3- or 4-morpholinobutyl, etc.,(1-pyrrolidinyl)(lower)alkyl such as (1-pyrrolidinyl)methyl, 1- or2-(1-pyrrolidinyl)ethyl, 1- or 2- or 3-(1-pyrrolidinyl)propyl, etc.,piperidino(lower)alkyl such as piperidino)methyl, 1- or2-(piperidino)ethyl, 1- or 2- or 3-(piperidino)propyl, etc., 2-(1-methyl-4-piperazinyl)ethyl, etc., and the like, and preferred one is2-morpholinoethyl.

"Heterocyclic" moiety of "heterocyclic-thio(lower)alkyl" for R², R_(b)², R_(c) ² and R_(d) ² and "heterocyclic-carbonyloxymethyl" for R⁵includes a heterocyclic group containing at least one hetero-atomselected from nitrogen, sulfur and oxygen atom, and may particularlyinclude saturated or unsaturated, monocyclic or polycyclic heterocyclicgroup, and more particularly N-containing heterocyclic group such asunsaturated 3 to 6 membered heteromonocyclic group containing 1 to 4nitrogen atoms, for example, pyrrolyl, pyrrolinyl, imidazolyl,pyrazolyl, pyridyl, and its N-oxide, pyrimidinyl, pyrazinyl,pyridazinyl, triazolyl, (e.g., 4H-1,2,4-triazolyl, 1H-1,2,3-triazolyl,2H-1,2,3-triazolyl, etc.), tetrazolyl (e.g., 1H-tetrazolyl,2H-tetrazolyl, etc.), etc.; saturated 3 to 6-membered heteromonocyclicgroup containing 1 to 4 nitrogen atoms (e.g., pyrrolidinyl,imidazolidinyl, piperidinyl, piperazinyl, etc.);

unsaturated condensed heterocyclic group containing 1 to 4 nitrogenatoms (e.g., indolyl, isoindolyl, indolizinyl, benzimidazolyl, quinolyl,isoquinolyl, indazolyl, benzotriazolyl, etc.);

unsaturated 3- to 6-membered heteromeoncyclic group containing 1 to 2oxygen atoms and 1 to 3 nitrogen atoms, for example, oxazolyl,isoxazolyl, oxadiazolyl, (e.g., 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl,1,2,5-oxadiazolyl, etc.), etc.;

saturated 3- to 6-membered heteromonocyclic group containing 1 to 2oxygen atoms and 1 to 3 nitrogen atoms (e.g., morpholinyl, etc.);

unsaturated condensed heterocyclic group containing 1 to 2 oxygen atomsand 1 to 3 nitrogen atoms (e.g., benzoxazolyl, benzoxadiazolyl, etc.);

unsaturated 3 to 6-membered heteromonocyclic group containing 1 to 2sulfur atoms and 1 to 3 nitrogen atoms, for example, thiazolyl,thiadiazolyl (e.g., 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl,1,2,5-thiadiazolyl, etc.), etc.;

saturated 3- to 6-membered heteromonocyclic group containing 1 to 2sulfur atoms and 1 to 3 nitrogen atoms (e.g., thiazolidinyl, etc.);

unsaturated condensed heterocyclic group containing 1 to 2 sulfur atomsand 1 to 3 nitrogen atoms (e.g., benzothiazolyl, benzothiadiazolyl,etc.) and the like; wherein said heterocyclic group may have at leastone suitable substituent such as lower alkyl (e.g., methyl, ethyl,propyl, isopropyl, butyl, isobutyl, pentyl, cyclopentyl, hexyl,cyclohexyl, etc.), or the like.

The "heterocyclic-thio(lower)alkyl" is particularly intended to mean alower alkyl which always bears the above-exemplified heterocyclic-thiogroup, and preferred heterocyclic-thio(lower)alkyl is unsaturated 3 to 6membered heteromonocyclic group containing 1 to 4 nitrogen atom(s) andhaving lower alkyl, and more preferred one is1-methyl-1H-tetrazol-5-ylthiomethyl.

Preferred heterocyclic-carbonyloxymethyl containing above-exemplifiedheterocyclic group is unsaturated 3 to 6-membered heteromonocyclic groupcontaining 1 to 4 nitrogen atoms, and more preferred one isnicotinoylmethyl.

"Lower alkylthio(lower)alkyl" for R², R_(c) ²,R_(d) ² and R_(e) ²includes lower alkylthiomethyl (e.g. methylthiomethyl, ethylthiomethyl,propylthiomethyl, butylthiomethyl, etc.), lower alkylthioethyl (e.g.,methylthioethyl, ethylthioethyl, propylthioethyl, isopropylthioethyl,butylthioethyl, pentylthioethyl, hexylthioethyl, etc.), loweralkylthiopropyl (e.g. ethylthipropyl, etc.), lower alkylthiobutyl (e.g.butylthiobutyl, etc.), and the like.

"Ar(lower)alkylthio(lower)alkyl" for R², R_(c) ², R_(d) ² and R_(e) ²includes phenyl(lower)alkylthio(lower)alkyl such asbenzylthio(lower)alkyl (e.g. benzylthiomethyl, benzylthioethyl,benzylthiopropyl, benzylthiobutyl, benzylthiopentyl, benzylthiohexyl,etc.) or the like.

"Arylthio(lower)alkyl" for R², R_(c) ², R_(d) ² and R_(e) ² includesphenylthio(lower)alkyl such as phenylthiomethyl, phenylthioethyl,phenylthiopropyl, phenylthiobutyl, phenylthiopentyl, phenylthiohexyl orthe like.

"Lower alkanoyloxy(lower)alkyl" for R² and R_(c) ², in which the loweralkanoyl moiety can be referred to the same ones as illustratedhereinafter, preferably includes formyloxymethyl, acetoxymethyl, 1- or2-formylethyl, 1- or 2-acetoxyethyl, 1- or 2-propionyloxyethyl, 1- or2-butyryloxy ethyl, 1- or 2-valeryloxyethyl, 1- or 2- or3-acetoxypropyl, 1- or 2- or 3- or 4-acetoxybutyl, and the like, andmore preferred one is 2-formyloxyethyl and 2-acetoxyethyl.

"Halo(lower)alkyl" for R_(a) ² is intended to meanhalogen-substituted-(lower)alkyl group, in which the halogen is to bereferred to those as illustrated before, and preferred examples thereofmay be chloromethyl, 1- or 2-chloroethyl, 1- or 2 or 3-chloropropyl, 1-or 2- or 3- or 4-chlorobutyl, bromomethyl, 1- or 2-bromoethyl, and thelike, and more preferred one is 2-chloroethyl.

"Hydroxy(lower)alkyl" for R_(d) ² includes hydroxymethyl, 1- or2-hydroxyethyl, 1- or 2- or 3-hydroxypropyl, 1- or 2- or 3- or4-hydroxybutyl, and the like, and preferred one is 2-hydroxyethyl.

"Di(lower)alkoxymethyl" for R⁵ and R_(a) ⁵ includes dimethoxymethyl,diethoxymethyl, dipropoxymethyl, diisopropoxymethyl, and the like, andpreferred one is dimethoxymethyl and diethoxymethyl.

"Halo(lower)alkanoyloxymethyl" for R⁵, in which the halogen and loweralkanoyl moieties are to be referred to ones as illustrated hereinbeforerespectively, particularly includes fluoroacetoxymethyl,chloroacetoxymethyl, bromoacetoxymethyl, 2- or3-chloropropionyloxymethyl, 2- or 3-bromopropionyloxymethyl, 2- or 3- or4-chlorobutyryloxymethyl, and the like, and preferred one is2-chloroacetoxymethyl.

Lower alkanoyl moiety of the "lower alkanoyloxymethyl" for R⁵ mayincludes formyl, acetyl, propionyl, butyryl, valeryl, isovaleryl, or thelike.

"Lower alkoxyaroyloxymethyl" for R⁵ preferably includes mono- or di- ortri(lower)alkoxy arroyloxymethyl such as (mono-loweralkoxy)benzoyloxymethyl (e.g. 2- or 3- or 4-methoxybenzoyloxymethyl, 2-or 3- or 4-ethoxybenzoyloxymethyl, etc.), (di-loweralkoxy)benzoyloxymethyl (e.g. 2,3- or 3,4- or 2,4- or3,5-dimethoxybenzoyloxymethyl, 2,3- or 3,4- or 2,4- or3,5-diethoxybenzoyloxymethyl, etc.), (tri-lower alkoxy)benzoyloxymethyl(e.g. 2,3,4- or 3,4,5- or 2,3,5- or 2,4,5-trimethoxybenzoyloxymethyl,2,3,4- or 3,4,5- or 2,3,5- or 2,4,5-triethoxybenzoyloxymethyl, etc.),and the like, and more preferred one is3,4,5-trimethoxybenzoyloxymethyl.

"Lower alkanoyl(lower)alken-1-yl" for R⁵, R_(b) ⁵ and R_(d) ⁵ preferablyincludes ones, in which the alken-1-yl moiety comprises 2 to 6 carbonatoms and preferred one is 2-formylvinyl, 2-acetylvinyl, propionylvinyl,and the like, and preferred one is 2-formylvinyl.

"Halo(lower)alken-1-yl" for R⁵ and R_(d) ⁵ preferably includes mono- anddi-halo(lower)alken-1-yl group, in which the lower alken-1-yl moietycomprises 2 to 6 carbon atoms and more preferred one isdihalo(lower)alken-1-yl such as 2,2-dichlorovinyl, 2,2-dibromovinyl, orthe like.

"Cyano(lower)alken-1-yl" for R⁵ and R_(d) ⁵ preferably includes ones, inwhich the alken-1-yl moiety comprises 2 to 6 carbon atoms and morepreferred one is cyanovinyl.

"Hydroxy(lower)alken-1-yl" for R⁵ and R_(c) ⁵ preferably includes ones,in which the alken-1-yl moiety comprises 3 to 6 carbon atoms, andparticularly 3-hydroxy-1-(lower)alkenyl such as 3-hydroxy-1-propenyl,3-hydroxy-1-butenyl, 3-hydroxy-1-pentenyl, and the like, and morepreferred one is 3-hydroxy-1-propenyl.

"Lower alkyn-1-yl" for R⁵ and R_(e) ⁵ preferably includes ones, in whichthe alkyn-1-yl moiety comprises 2 to 6 carbon atoms, and particularlyethynyl, 1-propynyl, 1-butynyl, 3-methyl-1-butynyl, 1-pentynyl, and thelike, and more preferred one is ethynyl and 1- propynyl.

"[N-Lower alkyl-N-haloar(lower)alkyl]amino", [N-lower alkyl-N-loweralkylar(lower)alkyl]amino", [N-lower alkyl-N-loweralkoxyar(lower)alkyl]amino", "aroylamino," "a saturated N-containingheterocyclic group", "heterocyclic-thio" for R^(a) are to be referred tothe corresponding moieties of the groups as illustrated hereinbeforei.e., "[N-lower alkyl-N-haloar(lower)alkyl]amino(lower)alkyl", "[N-loweralkyl-N-lower alkoxyar(lower)alkyl]amino(lower)alkyl", "[N-loweralkyl-N-lower alkylar(lower)alkyl]amino(lower)alkyl","aroylamino(lower)alkyl" "saturated N-containingheterocyclic-(lower)alkyl" and "heterocyclic-thio(lower)alkyl",respectively.

"Halo(lower)alkanoyl", "lower alkanoyl", "(lower alkoxy)aryl" and"heterocyclic-carbonyl" for R^(b) and each to be referred to thecorresponding acyl moieties of the groups as illustrated hereinbefore,i.e. "halo(lower)alkanoyloxymethyl", "lower alkanoyloxymethyl", "loweralkoxyaroyloxymethyl" and "heterocyclic-carbonyloxymethyl",respectively.

"Aryl" for R^(c) includes phenyl, tolyl, xylyl, naphthyl, and the like,and preferred one is phenyl.

"Lower alkanoyl" for R^(e) includes straight and branched ones such asformyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl,hexanoyl or the like, and preferably straight one, and more preferablyformyl and acetyl.

The starting compounds of this invention include known and new ones, andwere prepared by the following reaction schemes or the similar methodthereto. ##STR13## wherein R¹, R³, R⁴ and R_(a) ⁵ are each as definedbefore, and

R^(2') is lower alkyl.

Processes for preparation of the dihydropyridine derivative (I) of thisinvention will be explained in details below.

(1) Process 1:

This process relates to a method for preparing a compound (I-1) byreacting a compound (I-A) with a nucleophile of the formula: R^(a) --H,wherein R^(a) is as defined before, or a salt thereof.

A salt of the nucleophile of the formula: R^(a) --H includes an alkalimetal salt such as sodium salt, potassium salt, etc., an alkaline earthmetal salt such as calcium salt, magnesium salt, etc., and the like.

This reaction can preferably be carried out in the presence of a base,suitable examples of which include an inorganic base such as an alkalimetal hydroxide, carbonate, bicarbonate, hydride or amide (e.g. sodiumhydroxide, potassium hydroxide, sodium carbonate, potassium carbonate,sodium bicarbonate, sodium hydride, sodium amide, etc.) or an organicbase such as an alkali metal alkoxide (e.g. sodium methoxide, sodiumethoxide, potassium ethoxide, lithium methoxide, etc.), a salt of anorganic acid (e.g. sodium acetate, potassium acetate, etc.), an amine orimine base (e.g. triethylamine, pyridine, picoline, N,N-dimethylaniline,N-methylpyrolidine, N-methylmorpholine, etc.) and the like.

Further, this reaction is preferably carried out in the presence of analkali metal iodide such as lithium iodide, sodium iodide or the like inaddition to the base. The reaction is usually carried out in a suitablesolvent such as chloroform, methylene chloride, benzene, acetone,diethyl ether, tetrahydrofuran, dimethylformamide, methanol, ethanolpropanol, isopropanol, water and other conventional solvent or anoptional mixture thereof.

The reaction temperature is not restrictive, and the reaction is usuallycarried out at room temperature, or under warming or heating.

(2) Process 2:

This process relates to a method for preparing a compound (I-2) byhydrolysing a compound (I-B).

The compound (I-B) can be prepared by the method as illustrated in theabove Process 1.

In this process, the di(lower)alkoxymethyl group for R_(a) ⁵ of thecompound (I-B) is transformed by hydrolysis into a formyl group.

Hydrolysis may be carried out in a conventional manner which isconventionally applied for cleavage of so-called an acetal function intothe corresponding carbonyl function and preferably, for example,hydrolysis is carried out by an acidic hydrolysis, i.e. in the presenceof an acid such as an inorganic acid (e.g. hydrochloric acid, sulfuricacid, etc.), an organic acid (e.g. formic acid, acetic acid,trifluoroacetic acid, p-toluenesulfonic acid, etc.) or an acidicion-exchange resin.

This hydrolysis may be carried out in a suitable conventional solventsuch as water, acetone, methyl ethyl ketone, dioxane, ethanol, methanol,N,N-dimethylformamide, or dimethylsulfoxide, an optional mixture thereofor a buffer solution thereof. The reaction temperature is notrestrictive, and the reaction is usually conducted under cooling, atroom temperature or under somewhat elevated temperature.

(3) Process 3:

This process relates to a method for preparing a compound (I-3) byreacting a compound (I-C) with hydroxylamine or a salt thereof, and thenreacting the resultant product with a dehydrating agent.

According to this process, the formyl group of the starting compound(I-C) is transformed into the hydroxyiminomethyl group (the first step),and in succession said group is transformed into the cyano group (thesecond step).

The compound (I-C) can be prepared according to the above Process 2.

Preferable salt of hydroxylamine may be a salt with an acid such as aninorganic acid (e.g. hydrochloric acid, sulfuric acid, etc.) or anorganic acid (e.g. acetic acid, etc.).

(i) [Reaction of the first step]:

This reaction is carried out in a usual manner as so-called oximationreaction, for example, in the presence of a catalyst such as an acid(e.g. hydrochloric acid, hydrobromic acid, sulfuric acid, formic acid,acetic acid, p-toluenesulfonic acid, boron trifluoride, silicontetrachloride or titanium tetrachloride); in a basic condition broughtabout by a base, for example free hydroxylamine; or in an acidic orbasic conventional buffer solution. The reaction is usually conducted ina suitable conventional solvent such as water, dioxane, ethanol,methanol or dimethylformamide or an optional mixture thereof, and whenthe above acid is in liquid, it can also be used as a solvent.

The reaction temperature is not restrictive, and the reaction is usuallycarried out under cooling, at room temperature or under somewhatelevated temperature.

The reaction product of the first step is subjected to the followingsecond step with or without isolation.

(ii) [Reaction of the second step]:

Suitable example of the dehydrating agent used in this step includesconventional organic or inorganic ones such as an inorganic acid (e.g.sulfuric acid, phosphoric acid, polyphosphoric acid, etc.), an organicacid (e.g. formic acid, acetic acid, trifluoroacetic acid,ethanesulfonic acid, p-toluenesulfonic acid, etc.), an organic acidanhydride including lower alkanoic anhydride, arenoic anhydride, etc.,(e.g. acetic anhydride, benzoic anhydride, phthalic anhydride, etc.), anorganic acid halide (e.g. acetyl chloride, benzoyl chloride,trichloroacetyl chloride, mesyl chloride, tosyl chloride, ethylchloroformate, phenyl chloroformate, etc.); an inorganic halogencompound (e.g. thionyl chloride, phosphorus pentachloride, phosphorusoxychloride, phosphorus tribromide, stannic chloride, titaniumtetrachloride, etc.); a carbodiimide (e.g.N,N'-di-cyclohexylcarbodiimide,N-cyclohexyl-N'-morpholinoethylcarbodiimide, etc.),N,N'-carbonyldiimidazole;

pentamethyleneketene-N-cyclohexylimine; ethoxyacetylene;2-ethyl-7-hydroxyisoxazolium salt; other phosphorus compound (e.g.phosphorus pentoxide, polyphosphoric acid ethyl ester, triethylphosphateor phenylphosphate) and the like, or an optional mixture thereof. Whenan acid is used as the dehydrating agent, the reaction can also beconducted in the presence of its salt such as an alkali metal salt (e.g.sodium salt or potassium salt), and the like.

It is to be noted that the compound (I-3), wherein R¹, R³ and R⁴ areeach as defined hereinabove and R_(c) ² is loweralkanoyloxy(lower)alkyl, is to be prepared by treating the startingcompound (I-C), wherein R_(d) ² is hydroxy(lower)alkyl with the loweralkanoic acid anhydride mentioned above as the dehydrating agent.

This reaction is usually carried out in a conventional solvent such asdiethyl ether, dimethylformamide, pyridine, acetic acid, formic acid,benzene, carbon tetrachloride, chloroform, methylene chloride,tetrahydrofuran, dioxane, and the like, and usually carried out at roomtemperature or under heating, but the reaction temperature is notrestrictive to the above.

(4) Process 4:

This process relates to a method for preparing a compound (I-4) byreducing the compound (I-2).

The reduction can be carried out in a conventional manner which can beapplied for reduction of a formyl group into a hydroxymethyl group, andparticularly, the reduction is conducted by using a reducing agent suchas an alkali metal borohydride (e.g. lithium borohydride, sodiumborohydride, potassium borohydride, sodium cyanoborohydride, etc.) or bycatalytic reduction for which preferable catalyst may be palladiumcarbon, palladium chloride or rhodium carbon and the like. The reductionis usually carried out in a conventional solvent such as water,methanol, ethanol, isopropanol, dimethylformamide, tetrahydrofuran,etc., and the like. The reaction temperature is not restrictive, and thereaction is usually carried out under cooling, at room temperature or atsomewhat elevated temperature. And, the method of reduction mayoptionally be selected according to the kind of the compound (I-2).

(5) Process 5:

This process relates to a method for preparing a compound (I-5) byreacting a compound (I-D) with an acylating agent of the formula: R^(b)--OH, wherein R^(b) is as defined before, or a reactive derivative or asalt thereof.

The reactive derivative of the acylating agent of the formula: R^(b)--OH includes:

an acid halide such as acid chloride, acid bromide or the like;

an acid anhydride such as a mixed acid anhydride with an acid such assubstituted phosphoric acid (e.g., dialkylphosphoric acid,phenylphosphoric acid, diphenylphosphoric acid, dibenzylphosphoric acid,halogenated phosphoric acid, etc.), dialkylphosphorous acid, sulfurousacid, thiosulfuric acid, sulfuric acid, alkyl carbonate (e.g., methylcarbonate, ethyl carbonate, propyl carbonate, etc.), aliphatic caboxylicacid (e.g., pivalic acid, pentanoic acid, isopentanoic acid,2-ethylbutyric acid, trichloroacetic acid, etc.), aromatic carboxylicacid (e.g., benzoic acid, etc.); a symmetrical acid anhydride; or thelike.

an activated acid amide with a heterocyclic compound containing iminofunction such as imidazole, 4-substituted imidazole, dimethylpyrazole,triazole or tetrazole;

an activated ester (e.g., cyanomethyl ester, methoxymethyl ester,dimethylaminomethyl ester, vinyl ester, propargyl ester, p-nitrophenylester, 2,4-dinitrophenyl ester, trichlorophenyl ester, pentachlorophenylester, mesylphenyl ester, phenylazophenyl ester, phenyl thioester,p-nitrophenyl thioester, p-cresyl thioester, carboxymethyl thioester,pyranyl ester, pyridyl ester, piperidyl ester, 8-quinolyl thioester, oran ester with a N-hydroxy compound such as N,N-dimethylhydroxylamine,1-hydroxy-2-(1H)-pyridone, N-hydroxysuccinimide, N-hydroxyphthalimide,1-hydroxybenzotriazole, 1-hydroxy-6-chlorobenzotriazole, etc.); and thelike.

Suitable salts of the acylating agent include a salt with an inorganicbase such as an alkali metal salt (e.g., sodium or potassium salt,etc.), an alkaline earth metal salt (e.g., calcium or magnesium salt,etc.), a salt with an organic base such as trimethylamine,triethylamine, an acid addition salt (e.g., hydrochloride, etc.), andthe like. The suitable reactive derivative or salt of the acylatingagent can optionally be selected from the above, according to the kindsof the acylating agent, the starting compound (I-D) and/or reactioncondition (for example, solvent, reaction temperature, base, etc., asillustrated hereinbelow) to be used practically.

The reaction is preferably carried out in the presence of a base whichcan be referred to the same ones as those given in Process 1.

The reaction is usually carried out in a conventional solvent such aswater, acetone, dioxane, acetonitrile, chloroform, benzene, methylenechloride, ethylene chloride, tetrahydrofuran, ethyl acetate,N,N-dimethylformamide, pyridine or any other organic solvent or anoptional mixture thereof which does not adversely influence thereaction. Among these solvents, hydrophilic solvents may be used in amixture with water. The reaction temperature is not restrictive and thereaction is usually carried out under cooling to at ambient temperature.

Further, when the acylating agent is used in a form of the free acid orits salt in this reaction, the reaction is preferably carried out in thepresence of a condensing agent such as a carbodiimide compound (e.g.,N,N'-dicyclohexylcarbodiimide,N-cyclohexyl-N'-morpholinoethylcarbodiimide,N-cyclohexyl-N'-(4-diethylaminocyclohexyl)carbodiimide,N,N'-diethylcarbodiimide, N,N'-diisopropylcarbodiimide,N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide, etc.), a keteniminecompound (e.g., N,N'-carbonylbis(2-methylimidazole),pentamethyleneketene-N-cyclohexylimine,diphenylketene-N-cyclohexylimine, etc.); an olefinic or acetylenic ethercompound (e.g., ethoxyacetylene), β-chlorovinylethyl ether, a sulfonicacid ester of N-hydroxybenzotriazole derivative (e.g.,1-(4-chlorobenzenesulfonyloxy)-6-chloro-1H-benzotriazole, etc.), aphosphorus compound (e.g., trialkyl phosphite, ethyl polyphosphate,isopropyl polyphosphate, phosphoryl chloride, phosphorus trichloride,triphenylphosphine, etc.), thionyl chloride, oxalyl chloride,N-ethylbenzisoxazolium salt, N-ethyl-5-phenylisoxazolium-3'-sulfonate, areagent (referred to as so-called "Vilsmeier reagent") formed by thereaction of an amide compound (e.g. dimethylformamide,dimethylacetamide, N-methylformamide, etc.) with a halogen compound(e.g. thionyl chloride, phosphoryl chloride, phosgene, etc.).

(6) Process 6:

This process relates to a method for preparing a compound (I-6) bysubjecting a compound (I-E) to so-called Wittig-type reaction with aphosphorane compound of the formula: ##STR14## wherein R^(c), R^(d) andR^(e) are each as defined before or its reactive equivalent.

The reaction equivalent of the phosphorane compound includescorresponding phosphonium salt which can be represented by the formula:##STR15## wherein R^(c), R^(d) and R^(e) are each as defined above and Xis halogen, prepared by reacting a phosphine compound of the formula:(R^(c))₃ P with a halogen compound of the formula: ##STR16##

When the phosphonium salt in this reaction is used, the reaction isusually conducted in the presence of a strong base such as an alkalimetal compound, for example, an alkoxide (e.g. sodium ethoxide, lithiumethoxide, potassium t-butoxide, etc.), a phenoxide (e.g. lithiumphenoxide, etc.), an alkyl alkali metal compound (e.g. methyl lithium,butyl lithium, etc.), an aryl alkali metal compound (e.g., phenyllithium, etc.), an aralkyl alkali metal compound (e.g., triphenylmethylsodium, etc.), an alkali metal amide compound (e.g., N-methylanilinolithium, etc.) or the like.

This reaction is usually carried out in a suitable solvent such asmethylene chloride, ethylene chloride, benzene, toluene and otherconventional solvent or an optional mixture thereof.

The reaction temperature is not restrictive, and the reaction is usuallycarried out under cooling, at room temperature or somewhat elevatedtemperature.

It is to be noted that this reaction usually gives the cis- and transgeometrical isomers of the compound (I-6) due to the double bond to beformed, and these isomers are to be included within the scope of theobject compound (I-6).

(7) Process 7:

This process relates to a method for preparing a compound (I-7) byreacting a compound (I-F) with a strong base and then with electrophile.

The strong base preferably includes an alkali metal compound asexemplified in the foregoing Process 6, and more preferably an alkyllithium (e.g. n-butyl lithium, etc.) an aryl lithium (e.g. phenyllithium, etc.) and the like.

The electrophile includes a protic compound such as water, a lower alkylhalide (e.g. methyl iodide, ethyl bromide, etc.), or the like.

When water is used as the electrophile, the reaction is preferablyconducted in the presence of an acid such as an inorganic acid (e.g.hydrochloric acid, sulfuric acid, etc.) and an organic acid (e.g.p-toluenesulfonic acid, formic acid, etc.).

This reaction is usually carried out in a suitable solvent such astetrahydrofuran, diethyl ether, diisopropyl ether and other conventionalsolvent or an optional mixture thereof.

The reaction temperature is not restrictive, and the reaction is usuallycarried out under cooling.

In accordance with the present invention, the reaction product can beseparated and isolated from the reaction mixture and purified by methodscommonly used for this purpose, for instance, extraction with suitablesolvent, chromatography, precipitation, recrystallization and so on.

Suitable examples of a salt of the dihydropyridine compound include apharmaceutically acceptable salt such as an inorganic acid salt (e.g.hydrochloride, hydrobromide, phosphate, sulfate, etc.), an organic acidsalt (e.g. formate, acetate, fumarate, maleate, etc.), or an amino acidsalt (e.g. aspartate, glutamate, etc.).

(8) Process 8:

This process relates to a method for preparing a compound (I-8) byreacting a compound (I-G) with an amino compound (I-H).

Each of the starting compounds (I-G) and (I-H) includes cis and transisomers due to the double bond in their molecules, and both of such cisand trans isomers are equivalent in view of the compound (I-8), andtherefore, each isomer and optional mixtures of the isomers of thesestarting compounds (I-G) and (I-H) are to be included within the scopeof this process.

The reaction can be carried out at ambient temperature or under warmingor heating. The reaction can be conducted in the absence of a solvent,but may be conducted in a suitable solvent such as benzene, toluene,xylene, chloroform, carbon tetrachloride, methylene chloride, ethylenechloride, methanol, propanol, butanol, water or other conventionalsolvents. The reaction can be preferably accelerated in the presence ofan agent such as an acid (e.g. acetic acid), a base (e.g. pyridine orpicoline) or in a conventional buffer solution. These agents act as areaction accelerator and may also be used as a solvent when they are inliquid. The reactions can be also accelerated by warming or heating. Thereaction condition may vary according to the kind of the reactants,solvent and/or other agent as mentioned above to be used.

(9) Process 9:

This process relates to a method for preparing a compound (I-9) byreacting a compound (I-I) with an amino compound (I-J).

This process is substantially the same as Process 8, and accordingly canbe conducted by reacting the compounds (I-I) and (I-J) in the samemanner to those for the Process 8. That is, the same reaction conditions(e.g. reaction temperature, solvent, accelerator, etc.) and the samealternative reaction procedure as mentioned in the Process 8 are alsoapplied to this process.

The compound (I) thus obtained frequently includes at least one pair ofoptical isomers due to the asymmetric carbon atoms of the fourthposition of the 1,4-dihydropyridine nucleus, and of the lower alkylgroups and di(lower)alkoxymethyl for the groups in R², R³ and R⁵ and canexist as each optical isomer or a mixture thereof. A racemic compoundcan be resolved into each optical isomer by a conventional method forracemic resolution, such as a chemical resolution of the salts of thediastereomer with a conventional optically active acid (e.g. tartaricacid or camphor sulfonic acid, etc.).

As to utility of the object compound of this invention, it is to benoted that the compound (I) and a pharmaceutically acceptable saltthereof possess strong vasodilating activity and useful fortherapeutical treatment in hypertension and cardiovascular diseases suchas coronary insufficiency, angina pectoris or myocardial infarction.

Particularly, the compound (I), wherein R¹ is 3-nitro, R² is2-[N-methyl-N-(4-chlorobenzyl)amino]ethyl or2-[N-methyl-N-(3,4-dichlorobenzyl)amino]ethyl, R³ is ethyl, R⁴ is methyland R⁵ is cyano, has stronger vasodilating and anti-hypertensiveactivities, especially anti-hypertensive activity as compared with theknown compounds as herein above.

In addition to the above utility, it is also to be noted that thecompound (I), wherein R¹ is 3-nitro, R² is2-[N-methyl-N-(4-chlorobenzyl)amino]ethyl or2-[N-methyl-N-(3,4-dichlorobenzyl)amino]ethyl, R³ is ethyl, R⁴ is methyland R⁵ is diethoxymethyl or formyl, is useful not only as compoundhaving vasodilating and anti-hypertensive activities but also as anintermediate for preparing the more potent vasodilating andanti-hypertensive agent of this invention as illustrated hereinabove.

For therapeutical purpose, the dihydropyridine derivative (I) isadministered in daily dose of 0.1 to 500 mg, preferably 1 to 50 mg.

The pharmaceutical compositions of this invention comprise, as an activeingredient, the dihydropyridine derivative (I) or pharmaceuticallyacceptable salt thereof in an amount of about 0.01 mg. to about 500 mg.,preferably about 0.1 mg. to about 250 mg. per dosage unit for oral andparenteral use.

One skilled in the art will recognize that the amount of the activeingredient in the dosage unit form will be determined by considering theactivity of the ingredient as well as the size of the patient. Theactive ingredient may usually be formulated in a solid form such astablet, granule, powder, capsule, troche, lozenge or suppository, or asuspension or solution form such as syrup, injection, emulsion,lemonade, etc. and the like. A pharmaceutical carrier or diluentincludes solid or liquid non-toxic pharmaceutically acceptablesubstances. Examples of solid or liquid carriers or diluents arelactose, magnesium stearate, terra alba, sucrose, corn starch, talc,stearic acid, gelatin, agar, pectin, acacia, peanut oil, olive oil orsesame oil, cacao butter, ethyleneglycol or the other conventional ones.Similarly, the carrier or diluent may include a time delay material suchas glyceryl monostearate, glyceryl disterarate, a wax and the like.

For the purpose of showing the utility of the compound (I),thepharmacological test results of same represented compounds will be shownas follows.

Hypotensive effect:

Test Method;

Five Wistar rats were used per group. Each animal was immobilized in acage sized to the body. Blood pressure was measured at the femoralartery by means of a pressure transducer and recorded as electricalintegrated values of mean arterial pressure, and the heart rate wasdetermined by a pulse wave detector. Operation for the catheterizationwas performed under light anesthesia with ether. The test compound wasadministered orally 3 hrs after completion of the operation.

Test Compound;

Compound A (reference compound): 2-(N-benzyl-N-methylamino)ethyl esterof6-cyano-5-ethoxycarbonyl-2-methyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylicacid.

Compound B: 2-[N-(4-Chlorobenzyl)-N-methylamino]-ethyl ester of6-cyano-5-ethoxycarbonyl-2-methyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylicacid.

Compound C: Hydrochloride of2-[N-(3,4-dichlorobenzyl)-N-methylamino]ethyl ester of 6- cyano-b5-ethoxycarbonyl-2-methyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylicacid, hydrochloride.

Test Result;

Mean values of Δ Maximum Decrease of blood pressure (mmHg) were shown inthe following table.

    ______________________________________                                                   Dose                                                               Compound     1 mg/kg    10 mg/kg                                              ______________________________________                                        A            -11.0 ± 3.2                                                                           -42.4 ± 0.9                                        B            -29.2 ± 2.1                                                                           -63.6 ± 3.5                                        C            -25.6 ± 1.7                                                                           -56.6 ± 0.8                                        ______________________________________                                    

The following Examples are given for the purpose of illustrating thesyntheses of some specific compound of the present invention.

PREPARATION OF THE STARTING COMPOUND Preparation

(1) To a solution of 2-cyanobenzaldehyde (6.69 g) and 2-ethylthioethylacetoacetate (10.5 g) in benzene (30 ml) was added eight times asolution of acetic acid (30 mg) and piperidine (28 mg) in benzene (0.2ml) at intervals of half an hour with stirring, and the stirring wascontinued for 25 minutes, After adding benzene (50 ml) to the reactionmixture, the solution was washed with water until the neutral solutionwas obtained and then dried. The solvent was removed by distillationunder reduced pressure to give an oil (16.28 g), which waschromatographed over silica gel (500 g) with chloroform as an eluent,and the fractions containing a desired compound were collected andevaporated to dryness under reduced pressure to give 2-ethylthioethyl2-(2-cyanobenzylidine)acetoacetate (a mixture of cis and trans isomers)(16.28 g).

    ______________________________________                                        N.M.R.                                                                        δppm (CDCl.sub.3):                                                                1.21 (t, J = 7Hz)       2.43 (s)                                                                 (3H),          (3H),                                       1.27 (t, J = 7Hz)       2.27 (s)                                            2.63 (2H, t, J = 7Hz), 2.71 (2H, q, J = 7Hz),                                 4.25 (t, J = 7Hz)                                                                              (2H)                                                         4.37 (t, J = 7Hz)                                                             7.3-7.7 (4H, m),                                                                           7.73 (s)                                                                                    (1H)                                                            7.81 (s)                                                 ______________________________________                                    

The following starting compounds were obtained in substantially the samemanner as that of Preparation (1).

(2) 2-Benzylthioethyl 2-(2-cyanobenzylidene)acetoacetate (a mixture ofcis and trans isomers).

    ______________________________________                                        N.M.R.                                                                        δppm                                                                    (CDCl.sub.3):                                                                        2.33 (s)              2.4-2.9 (2H, m),                                                       (3H),                                                          2.49 (s)                                                                      3.68 (s)              4.28 (t, J = 7Hz)                                                      (2H),                 (2H),                                    3.77 (s)              4.36 (t, J = 7Hz)                                       7.25-7.8       (9H, m),                                                                             7.82 (s)                                                                                     (1H).                                                          7.91 (s)                                         ______________________________________                                    

(3) 2-Phenylthioethyl 2-(2-cyanobenzylidene)acetoacetate (a mixture ofcis and trans isomers).

    ______________________________________                                        N.M.R.                                                                        δppm                                                                    (CDCl.sub.3):                                                                           2.32 (s)           3.08 (t, J = 7Hz)                                                        (3H),               (2H),                                       2.50 (s)           3.23 (t, J = 7Hz)                                        4.37 (t, J = 7Hz)                                                                              (2H),                                                        4.44 (t, J = 7Hz)                                                             7.15-7.8 (9H, m),                                                             7.84 (s)                                                                                       (1H).                                                        7.88 (s)                                                              ______________________________________                                    

(4) 2-Ethylthioethyl 2-(2-trifluoromethylbenzylidene)-acetoacetate (amixture of cis and trans isomers).

    ______________________________________                                        N.M.R. δppm (CCl.sub.4):                                                             1.0-1.8 (3H, m),                                                                          2.1 (s)                                                                                   (3H),                                                             2.4 (s)                                                           2.0-3.0 (4H, m),                                                                          4.0-4.4     (2H, m),                                              7.3-8.0 (5H, m)                                                  ______________________________________                                    

PREPARATION OF THE OBJECT COMPOUND Example 1

(1) A mixture of 2-chloroethyl ester of5-ethoxycarbonyl-6-diethoxymethyl-2-methyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylicacid (8.08 g.), N-(4-chlorobenzyl)-N-methylamine (3.80 g), triethylamine(2.47 g) and sodium iodide (0.24 g) in propyl alcohol (15 ml) wasstirred at ambient temperature for 15 hours. After removal of thesolvent from the reaction mixture, water and ethyl acetate were added tothe residue. The organic layer was separated and washed with water. Thewashings and the remaining aqueous layer were combined and extractedwith ethyl acetate. The combined extract was washed with a saturatedaqueous solution of sodium chloride, dried and then evaporated todryness under reduced pressure to give an oil (11.13 g) of2-[N-(4-chlorobenzyl)-N-methylamino]ethyl ester of5-ethoxycarbonyl-6-diethoxymethyl-2-methyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylicacid.

N.M.R.

δppm (CDCl₃): 2.19 (3H, s), 2.36 (3H, s), 3.43 (2H, s)

The following compounds were obtained in substantially the same manneras that of Example 1-1).

(2) 2-[N-(3,4-Dichlorobenzyl-N-methylamino]ethyl ester of5-ethoxycarbonyl-6-diethoxymethyl-2-methyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylicacid.

N.M.R.

δppm (CDCl₃): 2.19 (3H, s), 2.41 (3H, s), 3.41 (2H, s)

(3) 2-Phthalimidoethyl ester of 5-ethoxycarbonyl-6-diethoxymethyl-2-methyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylicacid, mp 99°-101° C. (4) 2-Morpholinoethyl ester of5-ethoxycarbonyl-6-diethoxymethyl-2-methyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylicacid, mp 107°-108.5° C.

(5) 2-(1-Methyl-1H-tetrazol-5-ylthio)ethyl ester of5-ethoxycarbonyl-6-diethoxymethyl-2-methyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylicacid, mp 124.5°-126° C.

(6) 2-[N-Methyl-N-(4-methylbenzyl)amino]ethyl ester of4-(2-cyanophenyl)-5-ethoxycarbonyl-6-diethoxymethyl-2-methyl-1,4-dihydropyridine-3-carboxylicacid.

N.M.R.

δppm (CDCl₃): 1.0-1.4 (9H, m), 2.13 (3H, s), 2.29 (3H, s), 2.33 (3H, s),2.64 (2H, t, J=6.5 Hz), 3.41 (2H, s), 3.4-3.9 (4H, m), 4.13 (2H, q,J=6.5 Hz), 4.20 (2H, t, J=6.5 Hz), 5.38 (1H, s) 6.24 (1H, s), 6.80 (1H,broad s), 7.0-7.6 (8H, m).

(7) 2-[N-(4-Methoxybenzyl)-N-methylamino]ethyl ester of4-(2-cyanophenyl)-5-ethoxycarbonyl-6-diethoxymethyl-2-methyl-1,4-dihydropyridine-3-carboxylicacid.

N.M.R.

δppm (CDCl₃): 1.1-1.4 (9H, m), 2.15 (3H, s), 2.35 (3H, s), 2.65 (2H, t,J=6 Hz), 3.41 (2H, s), 3.5-4.3 (6H, m), 3.79 (3H, s), 5.38 (1H, s), 6.25(1H, s), 6.5-7.6 (8H, m)

(8) 2-[N-(4-Chlorobenzyl)-N-methylamino]ethyl ester of4-(2-cyanophenyl)-5-ethoxycarbonyl-6-diethoxymethyl-2-methyl-1,4-dihydropyridine-3-carboxylicacid.

N.M.R.

δppm (CDCl₃): 1.1-1.5 (9H, m), 2.17 (3H, s), 2.36 (3H, s), 2.66 (2H, t,J=6 Hz), 3.44 (2H, s), 3.4-4.1 (6H, m), 4.23 (2H, t, J=6 Hz), 5.41 (1H,s), 6.28 (1H, s), 6.83 (1H, broad s), 7.0-7.6 (8H, m)

(9) 2-[N-(3,4-Dichlorobenzyl)-N-methylamino]ethyl ester of4-(2-cyanophenyl)-5-ethoxycarbonyl-6-diethoxymethyl-2-methyl-1,4-dihydropyridine-3-carboxylicacid.

N.M.R.

δppm (CDCl₃): 1.1-1.5 (9H, m), 2.15 (3H, s), 2.38 (3H, s), 2.66 (2H, t,J=6 Hz), 3.42 (2H, s), 3.4-4.1 (6H, m), 4.23 (2H, t, J=6 Hz), 5.38 (1H,s), 6.25 (1H, s), 6.81 (1H, broad s), 6.9-7.6 (7H, m)

Example 2

(1) A mixture of 2-[N-(4-chlorobenzyl)-N-methylamino]ethyl ester of5-ethoxycarbonyl-6-diethoxymethyl-2-methyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylicacid (11.13 g) and 6N hydrochloric acid (11 ml) in acetone (120 ml) wasstirred at ambient temperature for 2 hours. After removal of acetonefrom the reaction mixture, to the residue was added water. The aqueoussolution was extracted twice with chloroform, and the combined extractwas washed with an aqueous solution of sodium bicarbonate and thendried. After removal of the solvent under reduced pressure, theresultant reddish oily residue was pulverized and washed with diethylether. The powder was neutralized with an aqueous solution of sodiumbicarbonate and extracted twice with ethyl acetate. The combined extractwas washed with an aqueous solution of sodium chloride and then dried,followed by removing the solvent under reduced pressure to give an oil(8.54 g).

A part (2.05 g) of this oil was chromatographed over silica gel (60 g)and eluted with a mixture of benzene and ethyl acetate (5:1 by volume)as an eluent, and the fractions containing a desired compound werecollected. The solvent was removed by distillation under reducedpressure to give oily 2-[N-(4-chlorobenzyl)-N-methylamino]ethyl ester of5-ethoxycarbonyl-6-formyl-2-methyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylicacid (0.68 g). This oily product was crystallized from small amount ofdiisopropyl ether and recrystallized from the same solvent to providethe purified same product, mp 84°-84.5° C.

The following compounds were obtained in substantially the same manneras that of Example (2-1).

(2) 2-[N-(3,4-Dichlorobenzyl)-N-methylamino]ethyl ester of5-ethoxycarbonyl-6-formyl-2-methyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylicacid, mp 104°-105° C.

(3) 2-Phthalimidoethyl ester of5-ethoxycarbonyl-6-formyl-2-methyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylicacid, mp 168°-170° C.

(4) 2-Morpholinoethyl ester of5-ethoxycarbonyl-6-formyl-2-methyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylicacid.

N.M.R.

δppm (CDCl₃): 1.32 (3H, t, J=7 Hz), 2.2-2.7 (9H, m), 3.5-3.8 (4H, m),4.0-4.4 (4H, m), 5.26 (1H, s), 7.2-8.2 (5H, m), 10.45 (1H, s)

(5) 2-(1-Methyl-1H-tetrazol-5-ylthio)ethyl ester of5-ethoxycarbonyl-6-formyl-2-methyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylicacid, mp 158°-159.5° C.

(6) 2-[N-Methyl-N-(4-methylbenzyl)amino]ethyl ester of4-(2-cyanophenyl)-5-ethoxycarbonyl-6-formyl-2-methyl-1,4-dihydropyridine-3-carboxylicacid.

N.M.R.

δppm (CDCl₃): 1.26 (3H, t, J=7.5 Hz), 2.13 (3H, s), 2.28 (3H, s), 2.38(3H, s), 2.66 (2H, t, J=6 Hz), 3.43 (2H, s), 4.23 (2H, q, J=7.5 Hz),4.23 (2H, t, J=6 Hz), 5.49 (1H, s), 6.9-7.7 (9H, m), 10.52 (1H, s)

(7) 2-[N-(4-Methoxybenzyl)-N-methylamino]ethyl ester of4-(2-cyanophenyl)-5-ethoxycarbonyl-6-formyl-2-methyl-1,4-dihydropyridine-3-carboxylicacid.

N.M.R.

δppm (CDCl₃): 1.28 (3H, t, J=7 Hz), 2.17 (3H, s), 2.43 (3H, s), 2.68(2H, t, J=6.5 Hz), 3.44 (2H, s), 3.80 (3H, s), 4.25 (2H, t, J=6.5 Hz),4.27 (2H, q, J=7 Hz), 5.50 (1H, s), 6.7-7.7 (9H, m), 10.53 (1H, s)

(8) 2-[N-(4-Chlorobenzyl)-N-methylamino]ethyl ester of4-(2-cyanophenyl)-5-ethoxycarbonyl-6-formyl-2-methyl-1,4-dihydropyridine-3-carboxylicacid.

N.M.R.

δppm (CDCl₃): 1.28 (3H, t, J=7.5 Hz), 2.17 (3H, s), 2.42 (3H, s), 2.67(2H, t, J=6 Hz), 3.43 (2H, s), 4.23 (2H, t, J=6 Hz), 4.25 (2H, q, J=7.5Hz), 5.48 (1H, s), 7.00 (1H, broad s), 7.1-7.7 (8H, m), 10.52 (1H, s)

(9) 2-[N-(3,4-Dichlorobenzyl)-N-methylamino]ethyl ester of4-(2-cyanophenyl)-5-ethoxycarbonyl-6-formyl-2-methyl-1,4-dihydropyridine-3-carboxylicacid.

N.M.R.

δppm (CDCl₃): 1.28 (3H, t, J=6.5 Hz), 2.16 (3H, s), 2.44 (3H, s), 2.68(2H, t, J=5.5 Hz), 3.42 (2H, s), 4.0-4.4 (4H, m), 5.47 (1H, s), 6.9-7.6(8H, m), 10.53 (1H, s)

Example 3

() A mixture of 2-[N-(4-chlorobenzyl)-N-methylamino]ethyl ester of5-ethoxycarbonyl-6-formyl-2-methyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylicacid (6.5 g), hydroxylamine hydrochloride (1.0 g) and sodium acetate(1.48 g) in acetic acid (20 ml) was stirred at ambient temperature foran hour. To the reaction mixture was added acetic anhydride (4.29 g),and the mixture was stirred at ambient temperature for 2 hours and at100° C. for additional 4 hours. After removal of the acetic acid fromthe reaction mixture, to the residue was added an aqueous solution ofsodium bicarbonate and then extracted twice with ethyl acetate. Thecombined extract was washed with water, dried over magnesium sulfate andthen evaporated to dryness under reduced pressure to give an oilyresidue (6.54 g), which was chromatographed over silica gel (200 g) andeluted with a mixture of benzene and ethyl acetate (5:1 by volume) as aneluent. The fractions containing a desired compound were collected andevaporated to dryness under reduced pressure to give an orange-yellowishoil of 2-[N-(4-chlorobenzyl)-N-methylamino]ethyl ester of6-cyano-5-ethoxycarbonyl-2-methyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylicacid (3.15 g).

N.M.R.

δppm (CDCl₃): 1.28 (3H, t, J=7.5 Hz), 2.17 (3H, s), 2.40 (3H, s), 2.61(2H, t, J=6 Hz), 3.46 (2H, s), 4.21 (2H, t, J=6 Hz), 4.27 (2H, q, J=7.5Hz), 5.26 (1H, s), 7.3-8.2 (9H, m)

The product obtained above was transformed into its hydrochloride (2.31g) by reacting said product with an ethanol solution of hydrogenchloride in a conventional manner, followed by pulverizing with diethylether and recrystallizing from an aqueous ethanol, mp 223°-225° C.(dec.).

The following compounds were obtained in substantially the same manneras that of Example (3-1).

(2) 2-[N-(3,4-Dichlorobenzyl)-N-methylamino]ethyl ester of6-cyano-5-ethoxycarbonyl-2-methyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylicacid hydrochloride, mp 233.5°-234° C. (dec.).

(3) 2-Phthalimidoethyl ester of6-cyano-5-ethoxycarbonyl-2-methyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylicacid, mp 158°-161° C.

(4) 2-Morpholinoethyl ester of6-cyano-5-ethoxycarbonyl-2-methyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylicacid hydrochloride, mp 235° C. (dec.).

(5) 2-(1-Methyl-1H-tetrazol-5-ylthio)ethyl ester of6-cyano-5-ethoxycarbonyl-2-methyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylicacid, mp 158°-160° C.

(6) 2-[N-Methyl-N-(4-methylbenzyl)amino]ethyl ester of6-cyano-4-(2-cyanophenyl)-5-ethoxycarbonyl-2-methyl-1,4-dihydropyridine-3-carboxylicacid hydrochloride, mp 230° C. (dec.).

(7) 2-[N-(4-Methoxybenzyl)-N-methylamino]ethyl ester of6-cyano-4-(2-cyanophenyl)-5-ethoxycarbonyl-2-methyl-1,4-dihydropyridine-3-carboxylicacid hydrochloride, mp 213°-214° C. (dec.).

(8) 2-[N-(4-Chlorobenzyl)-N-methylamino]ethyl ester of6-cyano-4-(2-cyanophenyl)-5-ethoxycarbonyl-2-methyl-1,4-dihydropyridine-3-carboxylicacid hydrochloride, mp 232°-233° C. (dec.).

(9) 2-[N-(3,4-Dichlorobenzyl)-N-methylamino]ethyl ester of6-cyano-4-(2-cyanophenyl)-5-ethoxycarbonyl-2-methyl-1,4-dihydropyridine-3-carboxylicacid hydrochloride, mp (240° C. (dec.).

(10) A solution of 2-hydroxyethyl ester of5-ethoxycarbonyl-6-formyl-2-methyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylicacid (5.22 g), hydroxylamine hydrochloride (1.08 g) and sodium acetate(1.48 g) in acetic acid (20 ml) was stirred at ambient temperature foran hour. To the reaction mixture was added acetic anhydride (5.79 g),and the mixture was stirred at ambient temperature for an hour and at95°-100° C. for additional 3 hours. After the reaction mixture wasallowed to cool to ambient temperature, the acetic acid was removed bydistillation under reduced pressure. The residue was dissolved in ethylacetate and washed with an aqueous solution of sodium bicarbonate andwater, dried over magnesium sulfate and evaporated to dryness underreduced pressure to give an oil (6.17 g), which was chromatographed oversilica gel (200 g) with a mixture of benzene and ethyl acetate (5:1 byvolume) as an eluent. The fractions containing a desired compound werecollected and evaporated to dryness under reduced pressure to give anorange-yellowish oil (3.23 g), which was crystallized from diethylether. The crude product (2.52 g) was recrystallized from diethyl etherto give yellowish crystals of 2-acetoxyethyl ester of6-cyano-5-ethoxycarbonyl-2-methyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylicacid (1.39 g), mp 114°-116° C.

Example 4

(1) To a solution of 2-morpholinoethyl ester of5-ethoxycarbonyl-6-formyl-2-methyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylicacid (3.42 g) in ethanol (60 ml) was added portionwise sodiumborohydride (0.27 g) under cooling at 0° C. over a period of half anhour with stirring, and the stirring was continued at the sametemperature for 2 hours. After the reaction mixture was slightlyacidified with 50% acetic acid, the ethanol was removed by distillationunder reduced pressure below 35° C. To the residue was added water andthen turned to be basic with an aqueous solution of sodium bicarbonate,and the separated oily substance was extracted twice with ethyl acetate.The combined extract was washed with a saturated aqueous solution ofsodium chloride and dried over magnesium sulfate to give a foamy oil(3.25 g), which was allowed to stand in a refrigerator over night andtriturated with diethyl ether to give a crude pale yellowish powder(2.56 g) of 2-morpholinoethyl ester of 5-ethoxycarbonyl-6-hydroxymethyl-2-methyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylicacid.

Yellowish powder (0.14 g) of the same product was recovered from thefiltrate. The combined powder was recrystallized from methanol to give apurified yellowish needles of the same product (1.69 g), mp 104°-106° C.

The following compound was obtained in substantially the same manner asthat of Example (4-1).

(2) Isopropyl ester of4-(2-chlorophenyl)-6-(3-hydroxy-1-propenyl)-5-methoxycarbonyl-2-methyl-1,4-dihydropyridine-3-carboxylicacid, mp 107°-110° C.

(3) 2-[N-Methyl-N-(4-methylbenzyl)amino]ethyl ester of4-(2-cyanophenyl)-5-ethoxycarbonyl-6-hydroxymethyl-2-methyl-1,4-dihydropyridine-3-carboxylicacid, mp 174°-176° C.

(4) 2-[N-(4-Methoxybenzyl)-N-methylamino]ethyl ester of4-(2-cyanophenyl)-5-ethoxycarbonyl-6-hydroxymethyl-2-methyl-1,4-dihydropyridine-3-carboxylicacid, mp 161°-163° C.

(5) 2-[N-(4-Chlorobenzyl)-N-methylamino]ethyl ester of4-(2-cyanophenyl)-5-ethoxycarbonyl-6-hydroxymethyl-2-methyl-1,4-dihydropyridine-3-carboxylicacid, mp 158°-159° C.

(6) 2-[N-(3,4-Dichlorophenyl)-N-methylamino]ethyl ester of4-(2-cyanophenyl)-5-ethoxycarbonyl-6-hydroxymethyl-2-methyl-1,4-dihydropyridine-3-carboxylicacid, mp 167°-169° C.

Example 5

(1) To a solution of isopropyl ester of6-hydroxymethyl-5-methoxycarbonyl-4-(2-methoxycarbonylphenyl)-2-methyl-1,4-dihydropyridine-3-carboxylicacid (2.60 g) in pyridine (20 ml) was added dropwise a solution ofacetyl chloride (0.83 g) in methylene chloride (10 ml) under cooling at0° C. over a period of a half an hour with stirring, and the stirringwas continued at the same temperature for 1.3 hours. After removal ofthe solvent, the residue was dissolved in ethyl acetate and washed with1N hydrochloride acid and water, dried over magnesium sulfate andevaporated to dryness under reduced pressure to give an oil (3.10 g),which was crystallized from diethyl ether. The yellowish crystals (2.29g) were recrystallized from methanol (9 ml) to provide yellowishcrystals (1.80 g) of isopropyl ester of6-acetoxymethyl-5-methoxycarbonyl-4-(2-methoxycarbonylphenyl)-2-methyl-1,4-dihydropyridine-3-carboxylicacid, mp 123°-124° C.

The following compounds were obtained in substantially the same manneras that of Example (5-1).

(2) Diethyl ester of6-chloroacetoxymethyl-2-methyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylicacid, mp 111.9°-113° C.

(3) Diethyl ester of6-(3,4,5-trimethoxybenzoyloxymethyl)-2-methyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylicacid, mp 152°-153.2° C.

(4) Diethyl ester of6-nicotinoyloxymethyl-2-methyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylicacid, mp 139°-140° C.

Example 6

(1) To a solution of 2-triphenylphosphoranylideneacetaldehyde (1.9 g) inmethylene chloride (15 ml) was added dropwise little by little asolution of isopropyl ester of4-(2-chlorophenyl)-6-formyl-5-methoxycarbonyl-2-methyl-1,4-dihydropyridine-3-carboxylicacid (2.14 g) in methylene chloride (25 ml) with stirring over a periodof 50 minutes, and the stirring was continued at ambient temperature foran hour. After removal of the methylene chloride from the reactionmixture, the residue was dissolved in benzene (10 ml) and subjected tocolumn chromatography over silica gel (120 g). Elution was carried outwith a mixture of benzene and ethyl acetate (10:1 by volume), andfractions containing a desired compound were collected and evaporated todryness under reduced pressure to give orange needles of isopropyl esterof4-(2-chlorophenyl)-6-(2-formylvinyl)-5-methoxycarbonyl-2-methyl-1,4-dihydropyridine-3-carboxylicacid (1.0 g), mp 179°-180.5° C.

The same product (0.1 g) was recovered from the mother liquor. Totalyield was 1.1 g.

The following compounds were obtained in substantially the same manneras that of Example (6-1).

(2) Isopropyl ester of6-(2-acetylvinyl)-4-(2-chlorophenyl)-5-methoxycarbonyl-2-methyl-1,4-dihydropyridine-3-carboxylicacid, mp 154°-156° C.

(3) Isopropyl ester of4-(2-chlorophenyl)-6-(2-cyanovinyl)-5-methoxycarbonyl-2-methyl-1,4-dihydropyridine-3-carboxylicacid, mp 159°-161.5° C.

(4) A mixture of isopropyl ester of4-(2-chlorophenyl)-6-formyl-5-methoxycarbonyl-2-methyl-1,4-dihydropyridine-3-carboxylicacid (0.472 g), triphenylphosphine (0.787 g) and carbon tetrachloride (2ml) was refluxed for 50 minutes under heating. After cooling, to thereaction mixture was added chloroform to dissolve it, washed three timeswith water and then evaporated to dryness to give a dark red-brown oil(1.74 g), which was chromatographed over silica gel (87 g) with amixture of benzene and ethyl acetate (20:1 by volume) as an eluent. Thefractions containing a desired compound were collected and evaporated todryness under reduced pressure to give a resinous substance, which wastriturated with diethyl ether and collected by filtration. Thesecrystals were recrystallized from diisopropyl ether to give yellowishneedles of isopropyl ester of4-(2-chlorophenyl)-6-(2,2-dichlorovinyl)-5-methoxycarbonyl-2-methyl-1,4-dihydropyridine-3-carboxylicacid, mp 153°-154° C.

The following compound was obtained in the same manner as that ofExample (6-4).

(5) Isopropyl ester of6-(2,2-dibromovinyl)-4-(2-chlorophenyl)-5-methoxycarbonyl-2-methyl-1,4-dihydropyridine-3-carboxylicacid, mp 155°-157° C.

Example 7

(1) To a solution of isopropyl ester of6-(2,2-dibromovinyl)-4-(2-chlorophenyl)-5-methoxycarbonyl-2-methyl-1,4-dihydropyridine-3-carboxylicacid (1.65 g) in tetrahydrofuran (30 ml) was added dropwise a solutionof n-butyllithium (5.95 ml) in tetrahydrofuran (8 ml) at -27° to -21° C.with stirring over a period of 20 minutes, and the stirring wascontinued for additional 20 minutes at the same temperature. To thereaction mixture was added diluted hydrochloric acid and then thetetrahydrofuran was removed therefrom. The residue was dissolved inethyl acetate and washed three times with water, dried and thenevaporated to dryness under reduced pressure. The residual reddish oilwas triturated with diisopropyl ether and allowed to stand for half anhour to provide an orange-yellowish powder (0.55 g), and the same powder(0.42 g) was recovered from the filtrate. The combined powder (0.97 g)was recrystallized from methanol to give orange-yellowish crystals ofisopropyl ester of 6-ethynyl-4-(2-chlorophenyl)-5-methoxycarbonyl-2-methyl-1,4-dihydropyridine-3-carboxylic acid (0.47 g). The same product(0.11 g) was recovered from the mother liquor. Total yield was 0.58 g.Additional recrystallization from methanol gave the purified same objectcompound, mp 172°-173.5° C.

(2) To a solution of isopropyl ester of6-(2,2-dibromovinyl)-4-(2-chlorophenyl)-5-methoxycarbonyl-2-methyl-1,4-dihydropyridine-3carboxylicacid (747.2 mg) in tetrahydrofuran (16 ml) was added dropwise a solutionof n-butyllithium (2.7 ml) in tetrahydrofuran (4 ml) under cooling at-20° C. with stirring over a period of 15 minutes, and the stirring wascontinued at the same temperature for about 25 minutes. To the resultantmixture was added dropwise a solution of methyl iodide (198.7 mg) intetrahydrofuran (1 ml) under cooling at -22° to -20° C. with stirringover a period of a 5 minutes and the stirring was continued at the sametemperature for an hour and for additional half an hour while thereaction temperature gradually elevated from -20° C. to -10° C. Dilutedhydrochloric acid was added to the reaction mixture and thetetrahydrofuran was removed by distillation therefrom under reducedpressure. The resultant residue was extracted with ethyl acetate, andthe extract was washed three times with water, dried and then evaporatedto dryness to give an oil (0.63 g), which was chromatographed oversilica gel (63 g) with a mixture of benzene and ethyl acetate (10:1 byvolume) as an eluent. The fractions containing a desired compound werecollected and evaporated to dryness to give a mixture (450 mg) ofisopropyl ester of6-ethynyl-4-(2-chlorophenyl)-5-methoxycarbonyl-2-methyl-1,4-dihydropyridine-3-carboxylicacid and isopropyl ester of6-(1-propynyl)-4-(2-chlorophenyl)-5-methoxycarbonyl-2-methyl-1,4-dihydropyridine-3-carboxylicacid (2:1 by N.M.R.).

Physical constant of the latter is as follows.

N.M.R.

δppm (CDCl₃): 1.05 (3H, d, J=6.5 Hz), 1.25 (3H, d, J=6.5 Hz), 2.04 (3H,s), 2.33 (3H, s), 3.66 (3H, s), 4.97 (1H, heptet, J=6.5 Hz), 5.42 (1H,s)

EXAMPLE 8

The following compounds were obtained in substantially the same manneras that of Example 1-1).

(1) 2-[N-(3,4-Dichlorobenzyl)-N-methylamino]ethyl ester of5-ethoxycarbonyl-6-diethoxymethyl-2-methyl-4-(2-trifluoromethylphenyl)-1,4-dihydropyridine-3-carboxylicacid.

N.M.R.

δppm (CDCl₃): 1.07-1.36 (9H, m), 2.14 (3H, s), 2.33 (3H, s), 2.57 (2H,t, J=6 Hz), 3.39 (2H, s), 3.4-4.4 (8H, m), 5.62 (1H, broad s), 6.11 (1H,s), 6.72 (1H, s), 7.0-7.7 (7H, m)

(2) 2-[N-(4-Chlorobenzyl)-N-methylamino]ethyl ester of4-(2-trifluoromethylphenyl)-5-ethoxycarbonyl-6-diethoxymethyl-2-methyl-1,4-dihydropyridine-3-carboxylicacid.

N.M.R.

δppm (CDCl₃): 1.16 (t, J=6.5 Hz), (9H), 2.14 (3H, s), 1.23 (t, J=7 Hz)2.30 (3H, s), 2.57 (2H, t, J=6 Hz), 3.42 (s), (10H), 5.53-5.65 (1H, m),3.3-4.3 (m) 6.09 (1H, s), 6.68 (1H, broad), 7.1-7.6 (8H, m)

EXAMPLE 9

The following compounds were obtained in substantially the same manneras that of Example 2-1).

(1) 2-[N-(3,4-Dichlorobenzyl)-N-methylamino]ethyl ester of5-ethoxycarbonyl-6-formyl-2-methyl-4-(trifluoromethylphenyl)-1,4-dihydropyridine-3-carboxylicacid.

N.M.R.

δppm (CDCl₃): 1.23 (3H, t, J=7.5 Hz), 2.17 (3H, s) 2.43 (3H, s), 2.60(2H, t, J=6.5 Hz) 3.43 (2H, s), 3.95-4.5 (4H, m), 5.71 (1H, broad s),7.0 (1H, m), 7.1-7.8 (7H, m), 10.29 (1H, s)

(2) Isopropyl ester of4-(2-biphenyl)-6-formyl-5-methoxycarbonyl-2-methyl-1,4-dihydropyridine-3-carboxylicacid, mp. 121.5°-123.5° C.

(3) 2-Ethylthioethyl ester of4-(2-cyanophenyl)-5-ethoxycarbonyl-6-formyl-2-methyl-1,4-dihydropyridine-3-carboxylicacid, mp 98°-100° C.

EXAMPLE 10

The following compounds were obtained in substantially the same manneras that of Example 3-1).

(1) 2-[N-(3,4-Dichlorobenzyl)-N-methylamino]ethyl ester of6-cyano-5-ethoxycarbonyl-2-methyl-4-(2-trifluoromethylphenyl)-1,4-dihydropyridine-3-carboxylicacid hydrochloride, mp 228°-229° C. (dec.).

(2) Isopropyl ester of4-(2-biphenylyl)-6-cyano-5-methoxycarbonyl-2-methyl-1,4-dihydropyridine-3-carboxylicacid, mp 164.1°-165.8° C.

(3) 2-Ethylthioethyl ester of6-cyano-4-(2-cyanophenyl)-5-ethoxycarbonyl-2-methyl-1,4-dihydropyridine-3-carboxylicacid, mp 125°-127° C.

EXAMPLE 11

The following compounds were obtained in substantially the same manneras that of Example 4-1).

(1) 2-[N-(3,4-Dichlorobenzyl)-N-methylamino]ethyl ester of5-ethoxycarbonyl-6-hydroxymethyl-2-methyl-4-(2-trifluoromethylphenyl)-1,4-dihydropyridine-3-carboxylicacid, mp 135°-137° C.

(2) Isopropyl ester of4-(2-biphenylyl)-6-hydroxymethyl-5-methoxycarbonyl-2-methyl-1,4-dihydropyridine-3-carboxylicacid, mp 131.5°-132° C.

(3) 2-Ethylthioethyl ester of4-(2-cyanophenyl)-5-ethoxycarbonyl-6-hydroxymethyl-2-methyl-1,4-dihydropyridine-3-carboxylicacid, mp 85°-87° C.

EXAMPLE 12

The following compounds were obtained in substantially the same manneras that of Example 2-1).

(1) 2-[N-(4-Chlorobenzyl)-N-methylamino]ethyl ester of5-ethoxycarbonyl-4-(2-trifluoromethylphenyl)-6-formyl-2-methyl-1,4-dihydropyridine-3-carboxylicacid.

N.M.R.

δppm (CDCl₃): 1.25 (3H, t, J=7 Hz), 2.18 (3H, s), 2.42 (3H, s), 2.60(2H, t, J=6.5 Hz), 3.45 (2H, s), 3.9-4.4 (4H, m), 5.70 (1H, broad s),6.95 (1H, broad s), 7.2-7.7 (8H, m), 10.26 (1H, s)

(2) 2-Benzylthioethyl ester of4-(2-cyanophenyl)-5-ethoxycarbonyl-6-formyl-2-methyl-1,4-dihydropyridine-3-carboxylicacid.

N.M.R.

δppm (CDCl₃): 1.28 (3H, t, J=7 Hz), 2.43 (3H, s), 2.64 (2H, t, J=7 Hz),3.68 (2H, s), 4.21 (2H, t, J=7 Hz), 4.26 (2H, q, J=7 Hz), 5.48 (1H, s),7.01 (1H, broad s), 7.1-7.7 (9H, m), 10.51 (1H, s).

(3) 2-Phenylthioethyl ester of4-(2-cyanophenyl)-5-ethoxycarbonyl-6-formyl-2-methyl-1,4-dihydropropyridine-3-carboxylicacid, mp 108°-110° C.

(4) 2-Ethylthioethyl ester of5-ethoxycarbonyl-4-(2-trifluoromethylphenyl)-6-formyl-2-methyl-1,4-dihydropyridine-3-carboxylicacid.

N.M.R.

δpm (CCl₄): 1.0-1.5 (6H, m), 2.1-2.7 (4H, m), 3.8-4.3 (4H, m), 5.5-5.65(1H, m), 6.8-6.9 (1H, m), 7.0-7.7 (4H, m), 10.22 (1H, s)

EXAMPLE 13

The following compounds were obtained in substantially the same manneras that of Example 3-1).

(1) 2-[N-(4-chlorobenzyl)-N-methylamino]ethyl ester of6-cyano-5-ethoxycarbonyl-4-(2-trifluoromethylphenyl)-2-methyl-1,4-dihydropyridine-3-carboxylicacid hydrochloride, mp 226°-227° C. (dec.).

IR_(max) ^(Nujol) : 3190, 2700-2400, 2270, 1711, 1700, 1380, 1320, 1318,1310, 1279, 1215, 1165, 1130, 1106, 1038, 765 cm⁻¹

(2) 2-Benzylthioethyl ester of6-cyano-4-(2-cyanophenyl)-5-ethoxycarbonyl-2-methyl-1,4-dihydropyridine-3-carboxylicacid.

N.M.R.

δppm (CDCl₃): 1.25 (3H, t, J=7 Hz), 2.36 (3H, s), 2.50 (2H, t, J=6 Hz),3.66 (2H, s), 4.18 (2H, t, J=6 Hz), 4.23 (2H, q, J=7 Hz), 5.40 (1H, s),7.2-7.7 (10H, m)

(3) 2-Phenylthioethyl ester of6-cyano-4-(2-cyanophenyl)-5-ethoxycarbonyl-2-methyl-1,4-dihydropyridine-3-carboxylicacid, mp 126°-128.5° C.

(4) 2-Ethylthioethyl ester of6-cyano-5-ethoxycarbonyl-4-(2-trifluoromethylphenyl)-2-methyl-1,4-dihydropyridine-3-carboxylicacid, mp 81°-82° C.

EXAMPLE 14

The following compounds were obtained in substantially the same manneras that of Example 4-1).

(1) 2-Benzylthioethyl ester of 4-(2-cyanophenyl)-5-ethoxycarbonyl-6-hydroxymethyl-2-methyl-1,4-dihydropyridine-3-carboxylicacid, mp 121°-122° C.

(2) 2-Phenylthioethyl ester of4-(2-cyanophenyl)-5-ethoxycarbonyl-6-hydroxymethyl-2-methyl-1,4-dihydropyridine-3-carboxylicacid, mp 114°-116° C.

(3) 2-Ethylthioethyl ester of5-ethoxycarbonyl-4-(2-trifluoromethylphenyl)-6-hydroxymethyl-2-methyl-1,4,-dihydropyridine-3-carboxylicacid.

N.M.R.

δppm (CDCl₃): 1.15 (3H, t, J=6 Hz), 1.23 (3H, t, J=6.25 Hz), 2.3-3.2(4H, m), 2.65 (1H, t, J=6.25 Hz), 2.35 (3H, s), 3.8-4.6 (2H, m), 4.17(2H, t, J=6.25 Hz), 4.77 (2H, s), 5.7-5.8 (1H, m), 7.1-7.8 (5H, m)

EXAMPLE 15

(1) A mixture of 2-ethylthioethyl2-(2-trifluoromethylphenyl)acetoacetate (14.43 g) and ethyl3-amino-4,4-diethoxycrotonate (9.56 g) was gradually heated until 110°C. in the course of an hour and for additional 22 hours at the sametemperature. To the reaction mixture was added ethyl acetate, washedtwice with water and evaporated to dryness under reduced pressure togive an oil (16.4 g). This oil was chromatographed over silica gel(about 500 g) with a mixture of benzene and ethyl acetate (70:1, andthen 25:1) and then chloroform as an eluent to give crude2-ethylthioethyl ester of5-ethoxycarbonyl-6-diethoxymethyl-4-(2-trifluoromethylphenyl)-2-methyl-1,4-dihydropyridine-3-carboxylicacid.

N.M.R. δppm (CCl₄): 1.0-1.5 (12H, m), 2.3-2.8 (4H, m), 2.41 (3H, s),3.4-4.5 (8H, m), 5.5-5.6 (1H, m), 6.13 (1H, s), 6.55 (1H, s), 7.1-7.7(4H, m)

The following compounds were obtained in substantially the same manneras that of Example 15-1).

(2) 2-Ethylthioethyl ester of5-ethoxycarbonyl-6-diethoxymethyl-4-(2-cyanophenyl)-2-methyl-1,4-dihydropyridine-3-carboxylicacid.

N.M.R. δppm (CDCl₃): 1.23 (12H, t, J=7.5 Hz), 2.36 (3H, s), 2.58 (2H, t,J=7.5 Hz), 2.63 (2H, q, J=7.5 Hz), 3.4-3.9 (4H, m), 4.13 (2H, q, J=7.5Hz), 4.19 (2H, t, J=7.5 Hz), 5.37 (1H, s), 6.22 (1H, s), 6.80 (1H, broads), 7.3-7.7 (4H, m)

(3) 2-Benzylthioethyl ester of5-ethoxycarbonyl-6-diethoxymethyl-4-(2-cyanophenyl)-2-methyl-1,4-dihydropyridine-3-carboxylicacid.

    ______________________________________                                        N.M.R. δppm (CDCl.sub.3):                                                               1.26 (9H, t, J = 7Hz),                                                        2.38 (3H, s), 2.64 (2H, t,                                                  J = 7Hz), 3.5-4.0 (m)                                                                             (6H),                                                     3.7 (s)                                                                       4.15 (4H, q, J = 7Hz),                                                        5.39 (1H, s), 6.27 (1H, s),                                                   6.85 (1H, broad s),                                                           7.1-7.7 (9H, m)                                                 ______________________________________                                    

(4) 2-Phenylthioethyl ester of5-ethoxycarbonyl-6-diethoxymethyl-4-(2-cyanophenyl)-2-methyl-1,4-dihydropyridine-3-carboxylicacid.

N.M.R. δppm (CDCl₃): 1.22 (9H, t, J=7 Hz), 2.33 (3H, s), 3.11 (2H, t,J=7.5 Hz), 3.4-3.9 (4H, m), 4.07 (2H, t, J=7.5 Hz), 4.15 (2H, q, J=7Hz), 5.33 (1H, s), 6.22 (1H, s), 6.81 (1H, broad s), 7.1-7.7 (9H, m)

(5) Isopropyl ester of4-(2-biphenylyl)-5-methoxycarbonyl-6-dimethoxymethyl-2-methyl-1,4-dihydropyridine-3-carboxylicacid, mp 103°-108° C. was obtained by reacting isopropyl3-aminocrotonate and methyl2-(2-biphenylylmethylene)-4,4-dimethoxyacetoacetate, which was preparedaccording to the same manner to that of Preparation (1), insubstantially the same manner to that of Example 15-1).

What is claimed is:
 1. A compound of the formula: ##STR17## wherein R¹is cyano or trifluoromethyl,R² is [N-lower alkyl-N-mono- ordihalophenyl(lower)alkyl]amino(lower)alkyl; R³ and R⁴ are each loweralkyl, and R⁵ is formyl, di(lower) alkoxymethyl or hydroxymethyl,andpharmaceutically acceptable salt thereof.
 2. A compound according toclaim 1, whereinR¹ is cyano or trifluoromethyl, R² is [N-loweralkyl-N-mono- or dihalophenyl(lower)alkyl]amino(lower)alkyl, R³ and R⁴are each lower alkyl and R⁵ is hydroxymethyl, and pharmaceuticallyacceptable salt thereof.
 3. A compound according to claim 2, whereinR²is [N-lower alkyl-N-mono- or dihalobenzyl]-amino(lower)alkyl, and R¹,R³, R⁴ and R⁵ are each as defined in claim
 2. 4. A compound according toclaim 3, whereinR¹ is 2-cyano or 2-trifluoromethyl, R² is2-(N-methyl-N-4-mono- or 3,4-dichlorobenzylamino)ethyl, R³ is ethyl, R⁴is methyl and R⁵ hydroxymethyl.
 5. A compound according to claim 4,whereinR¹ is 2-cyano, R² is 2-(N-methyl-N-4-chlorobenzylamino)ethyl, R³is ethyl, R⁴ is methyl and R⁵ is hydroxymethyl, and its hydrochloride.6. A compound according to claim 4, whereinR¹ is 2-trifluoromethyl, R²is 2-(N-methyl-N-3,4-dichlorobenzylamino)ethyl, R³ is ethyl, R⁴ ismethyl, and R⁵ is hydroxymethyl.
 7. A pharmaceutical composition fortreatment of hypertension comprising, as an active ingredient, aneffective amount of the compound of claim 1, in association with anontoxic, pharmaceutically acceptable carrier or excipient.